ISSN 0972-0200
Recent Advances
Recent Developments in Retinoblastoma
Raksha Rao, Santosh G Honavar
National Retinoblastoma Foundation, Ocular Oncology Service, Centre for Sight,
Banjara Hills, Hyderabad, India
Abstract
Retinoblastoma represents 3% of all childhood cancers, and is
the most common intraocular malignancy of childhood. It is fatal
if untreated. The management of retinoblastoma has gradually
evolved over the past few decades, with an aim to not only preserve
life and eye, but also optimize residual vision. The treatment of
retinoblastoma is multimodal, with chemotherapy, focal treatment
including trans-pupillary thermotherapy (TTT), cryotherapy and
laser photocoagulation, radiation therapy and surgery, all playing
a vital role. Intravenous chemotherapy has been the mainstay of
treatment for the past two decades, and still continues to be the
most extensively used eye-saving modality of treatment. Periocular
and intravitreal chemotherapy have specific indications in the
management of retinoblastoma. Intra-arterial chemotherapy has
emerged as a promising alternative for advanced and refractory
retinoblastoma, both as a primary and secondary therapy. Recent
advances in genetics of retinoblastoma have also helped in improving
the overall clinical management of this malignancy.
Keywords: retinoblastoma, Intra-arterial chemotherapy, Intravitreal
chemotherapy, Periocular chemotherapy, genetics
Introduction
Retinoblastoma was first described by Pawius in the 16th
century.1 But it was not until 1809 that retinoblastoma
was discovered to originate from the retina, when
Wardrop performed meticulous dissection on eyes with
retinoblastoma, and called it fungus haematodes.1 He
suggested enucleation as a life-saving treatment for
retinoblastoma, and it was the most acceptable therapy
until the introduction of radiation therapy. X-rays to treat
retinoblastoma was pioneered in the early twentieth century
and was the sole eye-saving treatment until mid-90s when
the use of chemotherapy in retinoblastoma was introduced.
Since then, numerous advances in the eye-salvage treatment
of retinoblastoma have evolved. However, enucleation is
still indicated in advanced cases, and specific indications
necessitate the use of external beam radiotherapy (EBRT).
Herein we discuss some of the relevant aspects in the
management of retinoblastoma that have had a paradigm
change in the recent past.
Epidemiology of Retinoblastoma
The incidence of retinoblastoma is 1 in every 15000 to
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18000 live births.2 There is no variation in the number
among different races, although there is a diversity among
different countries. There are an estimated 5000 new cases
worldwide annually, with India alone contributing to 1500-
2000 cases. With increasing population in Asian and African
countries, the number of retinoblastoma patients is also
rising. Unfortunately, the mortality rate for retinoblastoma
is also higher in these countries, owing to delay in diagnosis,
advanced disease at presentation, lack of access to advanced
medical facilities, and absence of standard management
protocols.
Genetics of Retinoblastoma
Retinoblastoma is a malignancy associated with somatic
mutation or germline mutation.2,3 Knudson proposed the
two-hit hypothesis where he described the occurrence of
two consecutive mutations for the conversion of a normal
retinal cell into a malignant cell (Figure 1). In heritable
retinoblastoma, the first mutation is in the germ cell, and
this ‘first hit’ is carried in every cell in the body, making
them prone not only for retinoblastoma, but also for
other second cancers (most commonly pinealoblastoma,
osteosarcoma and soft tissue sarcomas).3 The ‘second hit’
occurring in the retinal cells during retinal development
causes retinoblastoma. In non-heritable retinoblastoma,
both hits occur in the retinal cell, and thus the mutation
is confined to one single cell in the retina. Heritable
retinoblastoma constitutes 30-40% of all retinoblastomas,
while the rest 60-70% are non-heritable. One-fourths of the
germline mutations are familial with autosomal dominant
inheritance pattern, and the others are de-novo non-familial
germline mutations.3
RB1 is a tumor suppressor gene that was identified in
association with retinoblastoma and it validated the
two hit hypothesis. RB1 gene is located in the long arm
of chromosome 13 (13q), and most of the mutations are
nonsense codons or frame shifts. Sometimes retinoblastomas
are caused by genomic deletion of chromosome 13q, a
syndrome known as RB1 gene deletion syndrome, where
Figure 1: Genetics of Retinoblastoma
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Recent Advances

the affected individual has varying degrees of dysmorphic

features and neurodevelopmental delays.2
Clinical Features
Retinoblastoma is usually diagnosed at an average age of 18
months, with 95% of children diagnosed by 5 years of age.
Germline retinoblastomas can present as early as first month
and sporadic retinoblastomas are detected at an average age
of 24 months.2 Retinoblastoma can be unilateral or bilateral.
All bilateral cases are positive for germline mutation,
whereas only 10-15% patients with unilateral retinoblastoma
carry a germline mutation. The most common presenting
symptom and sign is leukocoria. Strabismus is the second
Table 1. Clinical Features of Retinoblastoma
Leukocoria
Strabismus
Figure 2: Clinical presentation of retinoblastoma (A) Exophytic growth
Poor vision pattern with diffuse subretinal fluid (B) Endophytic growth pattern with
Red painful eye diffuse vitreous seeds (C) Advanced retinoblastoma with neovascular
glaucoma (D) Advanced retinoblastoma presenting as sterile orbital
Vitreous hemorrhage cellulitis
Phthisis bulbi the confines of the eye is known as orbital retinoblastoma
Sterile orbital cellulitis and this can occur when the tumor invades either the optic
Proptosis nerve, or full thickness of the sclera and beyond, and the
patient generally presents with proptosis.
most common sign. The other common clinical features are
as listed in (Table 1). Differential Diagnosis
A child with a suspicious retinoblastoma is best examined The most important differential diagnosis is Coats’
under anesthesia for a detailed fundus evaluation. disease.5 There are several other lesions that can simulate
Retinoblastoma typically manifests as a unifocal or retinoblastoma and are known as pseudoretinoblastomas.
multifocal, well-circumscribed, dome-shaped retinal mass The important differential diagnoses are listed in (Table 2).
with dilated retinal vessels. Although initially transparent
and difficult to visualize, it grows to become opaque and
Imaging
white. When small, the tumor is entirely intraretinal. As it
While the diagnosis of retinoblastoma is mostly clinical,
enlarges, it grows in a three-dimensional plane, extending
ancillary tests like ultrasonography, fluorescein angiography
away from the vitreous cavity (exophytic) or towards it
(endophytic).2 Table 2. Pseudoretinoblastoma
In the exophytic growth pattern, the tumor arises from the Coats’ disease
outer retinal layers and causes diffuse retinal detachment
Persistent fetal vasculature
(Figure 2A). It is most often associated with numerous small
subretinal seeds. In contrast, an endophytic retinoblastoma Vitreous hemorrhage
arises from the inner retinal layers, progressively fills the Toxocariasis
vitreous cavity, and causes vitreous seeding (Figure 2B). At Familial exudative vitreoretinopathy
times, the tumor maybe a combination of these two growth
patterns. Diffuse infiltrating retinoblastoma is a rare pattern Retinal detachment
of presentation where there is no obvious mass, only a flat Congenital cataract
retinal infiltration, and is acalcific. It is generally seen in older Coloboma
children, and the incidence is less than 2%. Diffuse anterior
retinoblastoma, a recent entity, is considered as an anterior Astrocytic hamartoma
variant of diffuse infiltrating retinoblastoma. It is thought to Combined hamartoma
arise from the most peripheral parts of retina with anterior Endogenous endophthalmitis
growth, and no retinal focus visible on examination.4
Patients with anterior extension of the tumor can present with Retinopathy of prematurity
white fluffy exudates in the anterior chamber resembling a Medulloepithelioma
hypopyon, called pseudohypopyon.2 Neovascularization X-linked retinoschisis
of iris and glaucoma are other clinical presentations seen
in patients with advanced tumor (Figure 2C). Orbital Incontinentia pigmenti
cellulitis-like picture occurs when a large tumor undergoes Juvenile xanthogranuloma
necrosis and induces inflammation in and around the eye Norrie’s disease
(Figure 2D). Retinoblastoma which has extended outside

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(FA), optical coherence tomography (OCT), computed Table 4. International Classification of Retinoblastoma
tomography (CT) and magnetic resonance imaging (MRI)
Grouping
aid in the documentation of the disease and differentiation
of pseudoretinoblastomas from retinoblastoma (Table 3).6,7 Group A: Small
Retinoblastoma ≤3 mm in size
tumor
CT scan also helps diagnose extraocular extension, while

Table 3. Role of Multimodal Imaging in Retinoblastoma Rb >3 mm,

Group B: Larger Macular location (≤3 mm to foveola),
Wide angle fundus camera that is used in
tumor Juxtapapillary location (≤1.5 mm to disc)
Ret Cam documenting fundus findings at each visit, and
Clear subretinal fluid ≤3 mm from margin
monitoring the treatment.
Detection of calcification, especially useful in Subretinal seeds ≤3 mm from retinal tumor
Group C: Focal
establishing diagnosis in an opaque media. Vitreous seeds ≤3 mm from retinal tumor
Ultrasonography seeds
Also used in tumor thickness measurement and Subretinal & Vitreous seeds ≤3 mm from retinal
monitoring the effects of treatment. tumor
Performed on the RetCam using a filter. Helps
Fluorescein Subretinal seeds >3 mm from retinal tumor
in the visualization of capillary drop-outs,
Angiography Group D: Diffuse Vitreous seeds > 3 mm from retinal tumor
neovascularization, recurrences and occlusive
(FA) seeds Subretinal & Vitreous seeds >3 mm from retinal
vasculopathy following IAC.
tumor
Used in documenting early tumors,
Hand-held differentiation from pseudoretinoblastomas
Rb occupying 50% globe
spectral domain like astrocytic hamartomas, detection of small
Neovascular glaucoma,
OCT (SD-OCT) recurrences and assessment of fovea for visual Group E:
Opaque media (from hemorrhage in anterior
potential Extensive
chamber, vitreous, or subretinal space)
retinoblastoma
Computed Detects calcification and aids in the identification Invasion of postlaminar optic nerve, choroid (2
Tomography of orbital and optic nerve extension, although mm), sclera, orbit, anterior chamber
(CT) less sensitive than MRI.
Magnetic Delineating the intraocular tumor extent and Staging
Resonance detection of optic nerve or scleral extension, and Unilateral or bilateral retinoblastoma and no
Imaging (MRI) disease staging Stage 0
enucleation
MRI is most appropriate to detect optic nerve invasion and Stage I Enucleation with complete histological resection
to screen for pinealoblastoma in heritable retinoblastoma. Stage II Enucleation with microscopic tumor residual
Grouping and Staging (anterior chamber, choroid, optic nerve, sclera)
The grouping system is for retinoblastomas confined
Stage III Regional extension
to the eye, where eye salvage is the end point, whereas A. Overt orbital disease
the staging system is for predicting survival in patients B. Preauricular or cervical lymph node extension
with retinoblastoma. International Classification of
Retinoblastoma (ICRB) was devised in 2003 and includes Metastatic disease
both grouping and staging.8 The grouping is based on the A. Hematogenous metastasis
tumor size, location, severity and presence of subretinal and 1. Single lesion
Stage IV 2. Multiple lesions
vitreous seeds (Table 4). B. CNS extension
1. Prechiasmatic lesiom
Management 2. CNS mass
Management of a child with retinoblastoma is aimed at 3. Leptomeningeal disease
achieving the three sequential goals of life salvage, eye
salvage and optimal vision. Management involves the
identification of the tumor group and stage, decision-
making regarding the appropriate therapeutic measure, and Table 5. Decision-making in the Management of Retinoblastoma:
meticulous follow-up for monitoring the treatment progress Treatment Options
and detection of any recurrence. Primary tumor: Options for treatment
While intravenous chemotherapy remains the most Unilateral advanced (D, E) IAC, IVC, Enucleation
extensively used modality of treatment, other tools Unilateral less advanced (A, B, C) IAC, IVC, Focal therapy
available for the therapeutic intervention in retinoblastoma
Bilateral advanced (D, E) IVC + POC
include chemotherapy using different delivery routes,
focal treatment with cryotherapy, TTT, and laser Bilateral less advanced (A, B, C) IVC
photocoagulation, radiotherapy by teletherapy (external Recurrent tumor: Options for treatment
beam) or brachytherapy (plaque radiotherapy), and Solid tumor IVC, IAC, Plaque radiation, Enucleation
enucleation (Table 5).
Subretinal seeds IVC, IAC
Vitreous seeds IVitC
Chemotherapy
In recent years, there has been a trend towards targeted

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therapy to manage retinoblastoma with minimal adverse

Table 7. Periocular Chemotherapy
effects on surrounding normal retina and general
systemic health. The use of intra-arterial chemotherapy Procedure:
(IAC), periocular chemotherapy (POC), and intravitreal POC is administered by posterior sub-Tenon injection of
chemotherapy (IVitC) has enabled to focus direct drug the chemotherapeutic drug in the quadrant closest to the
location of the vitreous seeds. Innovative delivery systems
delivery to the tumor. Unlike IVC which can be used in the
for POC include the use of episcleral implants, fibrin
primary management of all retinoblastomas, IAC, POC and
sealants and nanoparticles of the drug
IVitC have specific indications.
Drugs:
Intravenous Chemotherapy Carboplatin (1.5-2.0 mg)
Currently, IVC is the most widely used treatment in India Topotecan (1 mg)
(Table 6). Used as a combination triple drug therapy of Indication:
vincristine, etoposide and carboplatin, chemotherapy with Advanced groups D or E with diffuse vitreous seeds in
focal consolidation achieves excellent success rates in the which a higher local dose of chemotherapy is desired
primary management of retinoblastoma. Chemotherapy
Advantages:
alone can achieve an impressive tumor control in less
(1) Achieves rapid levels within the vitreous in 30 min and
advanced cases, with success rates of 100%, 93% and 90%
can last for hours
in ICRB groups A, B and C, respectively (Figures 3A- (2) Achieves doses that are six to ten times higher than that
D).9,10,11 Rates of regression of retinoblastoma and eye achieved by IVC
salvage with standard triple-drug chemotherapy have
been suboptimal for ICRB group D and E tumors. In Disadvantages:
(1) Orbital and eyelid edema and ecchymosis
group D eyes, approximately half of the eyes require either
(2) Orbital fat atrophy
EBRT or enucleation for tumor control.9 A combination of
(3) Muscle fibrosis leading to strabismus.
chemotherapy and radiation in eyes with vitreous seeds has
yielded globe salvage rates varying from 22-70%.12 Periocular

Table 6. Intravenous Chemotherapy

Procedure
IVC when given as a primary treatment for retinoblastoma causes
reduction in tumor volume, and this is known as chemoreduction
(CRD). Most commonly, a combination of three drugs of standard
dose (SD) is used, although high dose (HD) may be necessary in
advanced cases or tumors not responding to SD.
Drugs
Triple drug combination therapy of vincristine, etoposide and
carboplatin (VEC) is employed, generally given 4 weekly for 6
cycles.
Day 1: Vincristine + Etoposide + Carboplatin
Day 2: Etoposide
SD-VEC SD-VEC
Drug HD-VEC
(≥3 years of age) (< 3 years of age)
Vincristine* 1.5 mg/m2 0.05 mg/kg 0.025 mg/Kg
Etoposide 150 mg/m2 5 mg/kg 12 mg/Kg
Carboplatin 560 mg/m2 18.6 mg/kg 28 mg/Kg Figure 3: Standard-dose chemotherapy in retinoblastoma (A) A group B
eye (B) After 6 cycles of standard-dose chemotherapy (C) A group C eye
*maximum dose < 2 mg
with focal vitreous seeds (D) After 6 cycles of standard-dose chemotherapy
Indications:
(1) Primary tumor
carboplatin and topotecan injection also resulted in higher
(2) Recurrent tumor intravitreal drug level (Table 7). Transscleral penetration
(3) Recurrent subretinal seeds of posterior sub-Tenon carboplatin leads to augmented
(4) As adjuvant therapy in post-enucleation patients with high-risk vitreous concentration. High-dose chemotherapy with
features (discussed elsewhere)
concurrent periocular carboplatin has been tried as a
(5) Orbital retinoblastoma
(6) As palliative therapy in metastatic retinoblastoma primary management strategy, specifically in eyes with
Advantages: diffuse vitreous seeds.13 This has led to better tumor control
(1) Long-term tumor control in advanced cases, with 95% eye salvage rate in eyes with
(2) Reduces incidence of pinealoblastoma focal vitreous seeds and a 70% eye salvage rate in those with
(3) Reduces incidence of second cancers diffuse vitreous seeds (Figure 4A-D).13
(4) Reduces incidence of systemic metastasis
Disadvantages:
(1) Systemic side-effects including thrombocytopenia, leucopenia Intra-arterial Chemotherapy
and anemia IAC for the treatment of intraocular retinoblastoma was first
(2) Allergic reactions to carboplatin and etoposide performed by Algernon Reese with direct internal carotid
(3) Long-term effects include hearing loss, renal toxicity and artery injection of the alkylating agent triethylene melamine
secondary leukemia
in 1954. Suzuki & Kaneko described the technique of

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Figure 4: High-dose chemotherapy in retinoblastoma with periocular
chemotherapy (A) A group D eye with diffuse vitreous seeds (B) Clinical
regression after 6 cycles of high-dose chemotherapy with 3 doses of
concurrent periocular carboplatin (C) A group D eye with fine diffuse
vitreous seeds (D) Complete regression after 6 cycles of high-dose
chemotherapy with 2 doses of concurrent periocular carboplatin
‘selective ophthalmic artery infusion’ (SOAI) in 2004 by
the balloon technique, where a micro-balloon catheter is
positioned by a transfemoral artery approach at the cervical
segment of the internal carotid artery just distal to the
orifice for the ophthalmic artery.14 At this point, the balloon
catheter is inflated, and chemotherapy is injected with flow
thereby directed into the ophthalmic artery. The authors
noted there are several small, but nevertheless important,
branches proximal to the origin of the ophthalmic artery
(i.e. cavernous branches of the ICA) into which infused
chemotherapy could flow, and concluded that this infusion
method is not truly selective. In 2006, Abramson and
Gobin pioneered direct intra-arterial (ophthalmic artery)
infusion or superselective intra-arterial chemotherapy or
“chemosurgery”.15
Patient is examined under anesthesia by the treating
ocular oncologist. Documentation of each affected eye is
performed by wide-angle fundus photography, FFA and
B-scan ultrasonography. The decision to treat with IAC is
undertaken in consultation with an ocular oncology team,
an endovascular neurosurgeon and a paediatric oncologist.
The procedure is performed under general anesthesia using
a sterile technique (Figures 5A-D). Nasal decongestion
is achieved by topical decongestant drops or spray.
Anticoagulation with intravenous infusion of heparin is
delivered to a target activated clotting time of 2 to 3 times
baseline. Through a transfemoral approach, the ipsilateral
internal carotid artery is catheterized with a 4F pediatric
guide catheter. The arterial anatomy is visualized with
serial angiography runs, and the ostium of the ophthalmic
artery is superselectively catheterized with a Prowler 10
microcatheter by the peep-in technique. A superselective
injection through the microcatheter is performed to check
adequate positioning and assessing the amount of reflux,
if any, into the internal carotid artery before chemotherapy
is injected. Each chemotherapy dose is diluted in 30 ml
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Figure 5: Intra-arterial chemotherapy: Procedure in the cath lab (A)
Patient under general anesthesia with a transfemoral cathether (B) An
angiography performed at the beginning of the procedure, showing a
patent internal carotid artery (C) An angiography performed with the
microcatheter at the ostium of the ophthalmic artery, showing a patent
ophthalmic artery (D) Infusion of the chemotherapeutic drug through the
transfemoral cathether
of saline and administered in a pulsatile fashion over 30
minutes to prevent lamination of medication and loss
of dose to peripheral tributaries. Repeat angiography is
performed immediately after the procedure to ensure
patency of the vessels, and the catheter removed. At
the end of the procedure, the heparin is reversed with
intravenous protamine and hemostasis achieved with
manual compression of the femoral artery upon removal
of the catheter.13 The child is monitored for 6 hours before
discharge.
IAC has emerged as an effective treatment for advanced
retinoblastoma (Figures 6A-D). It is increasingly being used
in tumors as a primary treatment, especially in unilateral
retinoblastoma. It can be used as a secondary therapy for
those cases which have recurred or have not responded
adequately to IVC (Table 8). Shields et al observed 94%
globe salvage in group D eyes, and 91% vitreous seed
regression, when IAC was used as a primary therapy.16-18
In a study comparing 2-year ocular survival rate between
naïve eyes with vitreous seeds (IAC as a primary therapy)
and previously treated eyes with vitreous seeds (IAC as
a secondary therapy), Abramson et al observed that IAC
seemed to be more effective in eyes that have failed to
respond to previous therapies. In an overall study on IAC
in retinoblastoma, Abramson et al observed that eyes with
vitreous seeds tend to require higher treatment sessions and
doses, and multiple agents, as compared to eyes without
vitreous seeds.15
Intravitreal Chemotherapy
Vitreous seeds are aggregates of tumor cells found in the
avascular vitreous, which are relatively resistant to the
effect of intravenous chemotherapy due to lack of blood
supply (Table 9). These appear due to the disruption
of the apical tumor either spontaneously (primary) or
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Table 9. Vitreous Seeds: Classification

Primary VS Present at the initial diagnosis
Those which appear during
the course of treatment due
Secondary VS
to necrotic disruption of the
tumor
Primary VS which persist
Persistent VS
beyond chemoreduction
VS which appear after the
Recurrent VS
completion of chemoreduction
Seeds located ≤ 3 mm from the
Focal VS
main tumor
Seeds located >3 mm from the
Diffuse VS
tumor
Free-floating VS Seeds dispersed in the vitreous
Seeds present just anterior to
Figure 6: Intra-arterial chemotherapy in advanced retinoblastoma (A) A Pre-hyaloid VS
the hyaloid membrane
group D eye with diffuse vitreous seeds (B) After 3 cycles of intra-arterial
chemotherapy (C) A group E eye with a very large tumor and diffuse Seeds present just anterior to
Retro-hyaloid VS the internal limiting membrane
subretinal fluid (D) After 3 cycles of intra-arterial chemotherapy
of the retina
Table 8. Intra-arterial Chemotherapy
Minute VS formed following the
Procedure: Dust formation
apical disruption of the tumor
IAC involves the delivery of chemotherapeutic drugs directly
in the eye through a fluoroscopy-guided microcatheter into the Balls of VS resulting from clonal
ostium of the ophthalmic artery, and is done in a cath lab by Sphere formation
expansion of dust
an interventional neuroradiologist. IAC can be a one-, two- or
Massive VS resulting from the
three-drug regimen, and each drug is delivered slowly over 30 Cloud formation
disruption of the tumor
min in a pulsatile fashion. It is repeated every 4 weeks, and most
of the patients require 3 sessions to achieve complete tumor
treatment-induced necrosis (secondary). Suboptimal
regression.
concentration of chemotherapeutic agents in the vitreous
Drugs:
results in persistence of vitreous seeds.19 Refractory
Melphalan is the most extensively used drug in IAC, and
topotecan is added if there is extensive vitreous seeding. In vitreous seeds are the persistent or recurrent vitreous
advanced cases, three drugs including carboplatin are employed seeds which do not respond to the standard treatment
to ensure complete tumor control. modalities. Persistent seeds are those which are present
One-drug regimen: Melphalan (3-7.5 mg) during chemoreduction, and continue to persist after the
Two-drugs regimen: Melphalan (3-7.5 mg) + Topotecan (1-2 mg) completion of chemoreduction.20 Recurrent seeds are those
Three-drugs regimen: Melphalan (3-7.5 mg) + Topotecan (1-2
which appear after the completion of chemoreduction. IVitC
mg) + Carboplatin (15-50 mg)
achieves higher drug concentration within the vitreous and
Indication:
effectively causes regression of vitreous seeds, without
IAC can be used as a primary therapy, or secondary therapy in
eyes which have not achieved tumor control after intravenous associated systemic side effects. IVitC in retinoblastoma
chemotherapy. In general, it is preferred in children older than 4 was first introduced by Ericson and Rosengren using
months of age without a germline mutation. thiotepa in 1960. Methotrexate has also been tried as an
(1) Unilateral nongermline retinoblastoma intravitreal drug for retinoblastoma. In 1987, Inomata and
(2) Recurrent retinoblastoma following previous IVC or plaque Kaneko investigated the sensitivity of retinoblastoma to 12
radiotherapy
anticancer drugs and found that the retinoblastoma cells
(3) Recurrent extensive subretinal seeds not controlled by IVC
were most sensitive to melphalan in-vitro. Melphalan is
Advantages:
now the most extensively used drug to control the vitreous
(1) High intraocular concentration of the drug without
associated systemic adverse effects of the drugs disease in retinoblastoma (Table 10). Munier et al discussed
(2) Shorter time for tumor control a potentially safe technique to perform intravitreal injections
Disadvantages: to prevent extraocular extension of the tumor.21 They
(1) Expensive advocated the application of triple freeze-thaw cryotherapy
(2) Difficulty with catheterizations at the injection site to prevent egress of the tumor cells in the
(3) Vitreous hemorrhage needle track (Figure 7A-D).
(4) Branch retinal artery obstruction With melphalan, vitreous seed regression ranging from 85-
(5) Ophthalmic artery spasm with reperfusion 100% of eyes and globe salvage in 80-100% of eyes have been
(6) Ophthalmic artery obstruction
(7) Partial choroidal ischemia
reported.22-24 Intravitreal melphalan is given as a weekly
(8) Optic neuropathy injection until regression. The disadvantage of melphalan is
(9) Complications associated with the technique including a risk that it is not stable in solutions, and has to be used within
for brain vascular events, hypoxia, hypotension and bradycardia an hour of reconstitution of the drug. A combination of

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Table 10. Intravitreal Chemotherapy
Procedure:
Any intraocular procedure in retinoblastoma is generally
avoided for fear of extraocular extension of the tumor.
However, intravitreal injections by safety-enhanced technique
has proven to prevent this risk. The injection site is carefully
chosen after a thorough clinical examination to rule out the
presence of tumor, vitreous seeds or subretinal fluid at the
injection site. The injection is given using a 30 gauge needle
by the transconjunctival pars plana route. After injecting the
drug, the needle is withdrawn in the first ice ball formation of
the chemotherapy followed by injection site triple freeze-thaw
cryotherapy. This technique reduces the extraocular escape of
any tumor cell through the needle track.
Drugs:
Melphalan is the most widely used drug in IVitC, and topotecan
is generally added if there is extensive vitreous seeding.
Topotecan may also be used as a single drug.
Melphalan (20-30 μg)
Topotecan (20-30 μg)
Combination: Melphalan (20-30 μg) + Topotecan (20-30 μg)
Indication:
(1) Recurrent diffuse or focal vitreous seeds
(2) Persistent diffuse or focal vitreous seeds
Advantages:
(1) High intraocular concentration of the drug without
associated systemic adverse effects of the drugs
(2) Complications associated with POC avoided
Disadvantages:
(1) Extraocular extension of the tumor associated with an
improper technique
(2) Risk of endophthalmitis
Figure 7: Intravitreal chemotherapy: Safety-enhanced technique (A) Pars
plana intravitreal injection of topotecan at a dose of 30 μg in 0.15 ml with
a 30-gauge needle (B) Needle is withdrawn through the first ice ball of
the cryotherapy (C) Triple freeze-thaw cryotherapy at the injection site (D)
Forceps-assisted jiggling of the eyeball following the injection for an even
dispersion of the chemotherapeutic drug
intravitreal melphalan and topotecan has also been used
to achieve excellent regression in refractory vitreous seeds.
The authors have used topotecan as monotherapy in
achieving vitreous seed regression in 36 eyes (Figure 8A-D).
Topotecan is a very safe drug for intraocular use, is stable in
solution and can be given as a 3-weekly injection.
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Figure 8: Intravitreal chemotherapy with topotecan (A) Before and (B)
after 2 doses of intravitreal topotecan injections in an eye with recurrent
diffuse vitreous seeds after 9 cycles of chemotherapy (C) Before and (D)
after 2 doses of intravitreal topotecan injections for a massive recurrence
of diffuse vitreous seeds in a one-eyed patient
Radiation Therapy
Retinoblastoma is a highly radiosensitive tumor, and
radiation therapy can be curative. Radiation in the form
of EBRT was the most popular globe-salvage therapy in
retinoblastoma before the introduction of chemotherapy
in 1990s. Although it is no longer the primary modality
of treatment for retinoblastoma due to the associated
complications, it has its own therapeutic indications
(Table 11). Episcleral plaque radiotherapy is a form of
brachytherapy wherein the source of radiation is placed on
the episclera adjacent to the tumor, and the tumor absorbs
radiation, sparing other healthy ocular tissues from the ill-
effects of radiation (Table 12).25
Focal Therapy
Although episcleral plaque therapy may also be considered
as a form of focal therapy, the term generally refers to the
use of cryotherapy, TTT and laser therapy in the treatment of
retinoblastoma. These are generally used for consolidation
once the tumor has attained a considerably lower volume
with chemoreduction, usually after 2 or 3 cycles, or for the
treatment or small recurrent tumors of subretinal seeds.26-28
However, they can also be used as the sole therapy for small
retinoblastomas (Tables 13,14,15).
Enucleation
Enucleation is the oldest form of treatment for retinoblastoma,
and is still indicated in advanced cases.11 Unilateral disease
with no salvageable vision is best treated by enucleation
and the patient can be rid of the disease for life. Enucleation
is a simple procedure, although special precautions need to
be taken when handling an eye with retinoblastoma (Table
16). These are necessary to avoid accidental perforation that
can potentially cause orbital seeding of the tumor. Use of a
primary silicone or polymethylmethacrylate implant by the
myoconjunctival technique provides adequate static and
dynamic cosmesis. Porous polyethylene or hydroxyapatite
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Table 11. External Beam Radiation Therapy
Procedure:
Numerous methods and protocols to treat retinoblastoma with
EBRT have been described. Lens-sparing technique with electron
beam and photon beam using a linear accelerator has been
traditionally employed. Newer techniques using stereotactic
radiation therapy (SRT), intensity modulated radiation therapy
(IMRT) and proton therapy have been described. The standard
dose is 40-45 Gy, generally given in fractionated doses over 3-4
weeks.
Indication:
(1) HRF on pathology after enucleation (described elsewhere)
(2) As a part of multimodal management in orbital
retinoblastoma (described elsewhere)
(3) Tumor and/ or vitreous seeds refractory to other treatments
Advantages:
(1) Prevents orbital recurrence when given as an adjuvant
therapy for indications 1 and 2
(2) Excellent long-term tumor control when used for refractory
tumor/ vitreous seeds
Disadvantages:
(1) Orbital hypoplasia
(2) Secondary cancers in the field of radiation
(3) Cataract
(4) Dry eye syndrome
Table 12. Episcleral Plaque Brachytherapy
Procedure:
Radioisotopes like Iodine-125 and Ruthenium-106 that emit
radiation are used for the treatment of various ocular tumors
including retinoblastoma. I-125 emits gamma radiation, and
Ru-106 beta radiation, which can penetrate the tumor. For this,
the radioisotopes are loaded on an applicator (gold or silver),
and the plaque sutured onto the episclera. The duration of the
treatment is calculated by a radiation physicist, and the plaque is
removed at the end of the treatment duration.
Indication:
(1) Recurrent tumor that is > 3 mm in thickness which is not
suitable for treatment by other forms of focal therapy (TTT,
cryotherapy or laser photocoagulation)
Advantages:
(1) Direct treatment of the tumor with minimal scarring
(2) Deeper penetration as compared with other forms of focal
treatment
(3) Single treatment session
(4) Surrounding healthy tissue is not effected
(5) Overlying focal vitreous seeds are also treated
simultaneously
Disadvantages:
(1) Not effective in large recurrent tumors
(2) Not ideal in multifocal recurrences
(3) Delayed radiation-related complications like radiation
retinopathy
implants don’t offer additional advantage unless pegged,
and these are best avoided if a child is likely to need
adjuvant chemotherapy or EBRT following enucleation
since fibrovascular integration of these implants would be
impeded. An enucleated eyeball is always submitted for
pathology to assess for high risk factors (HRF). In a landmark
paper by Honavar et al, the need for adjuvant chemotherapy
has been emphasized to reduce the risk of secondary orbital
recurrence and systemic metastasis.29 The incidence of
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Table 13. Cryotherapy
Procedure:
Transscleral cryotherapy involves freezing the tumor under
visualization using indirect ophthalmoscopy. The cryoprobe
tip is centered directly under the tumor and the ice ball formed
on freezing should adequately cover the tumor and any focal
vitreous seeds. Triple freeze-thaw cycles of cryotherapy are
generally applied. Cryotherapy destroys the tumor cells
mechanically by disruption of the cell membranes during
thawing of the intracellular ice crystals. Typically the treatment
is repeated every 3-4 weeks.
Indication:
(1) Peripheral tumors <4 mm in diameter and <3 mm in thickness
(2) Subretinal seeds
Advantages:
(1) Treatment of focal vitreous seeds overlying the tumor
Disadvantages:
(1) Large area of retinal scarring
(2) Retinal breaks
Table 14. Transpupillary Thermotherapy
Procedure:
In thermotherapy, hyperthermia generated by infrared radiation
at subphotocoagulation levels destroys the tumor. A slow and
sustained temperature range of 40 to 60 degree C within the
tumor is generated using a semiconductor diode laser (810 nm)
delivered as a 1300-micron large spot and long burn duration
(1 minute) with indirect ophthalmoscope delivery system. The
tumor is heated until it turns a subtle gray. Complete tumor
regression can be achieved in over 85% of tumors using 3-4
sessions of thermotherapy. Using indocyanine green dye to
sensitize the tumor for TTT (ICG-enhanced TTT) is an effective
alternative for tumor control, particularly for small tumors that
show suboptimal response to standard TTT.
Indication:
(1) Small tumors which are 4 mm in diameter and 2 mm in
thickness
(2) Subretinal seeds
Advantages:
(1) Synergistic combination of thermotherapy with
chemoreduction protocol (chemothermotherapy), with
heat application amplifying the cytotoxic effect of platinum
analogues
Disadvantages:
(1) Focal iris atrophy
(2) Focal paraxial lens opacity
(3) Large area of retinal scarring
(4) Retinal traction and serous retinal detachment
metastasis was 4% in those who received adjuvant therapy,
compared with 24% in those who did not. Hence when HRF
is positive, adjuvant treatment with chemotherapy and/
or EBRT is indicated (Table 17). Adjuvant chemotherapy
consists of a combination of vincristine, etoposide and
carboplatin given 4-weekly for 6 cycles.29
Orbital Retinoblastoma
Orbital retinoblastoma is an advanced form of
retinoblastoma seen mostly in developing countries of
Asia and Africa. The incidence varies among different
countries, and is in the range of 18-40%.30 Orbital disease
can be classified as listed in (Table 18). Primary orbital

Recent Advances
Table 15. Laser Photocoagulation
Procedure:
Photocoagulation using argon green laser (532 nm) delivered
with an indirect laser delivery system causes tumor apoptosis.
Overlapping spots on the tumor edge are placed at a power
setting of 250-350 mw for 0.3-0.5 seconds. The treatment destroys
the tumor by restricting the blood supply to the tumor and also
by hyperthermia. Typically the treatment is repeated every 3-4
weeks
Indication:
(1) Small posterior tumors which are 4 mm in diameter and 2
mm in thickness
Advantages:
(1) Can be used when TTT is not available
Disadvantages:
(1) Retinal traction and serous retinal detachment
(2) Retinal vascular occlusion
(3) Retinal hole
(4) Large area of retinal scarring
(5) Not ideal while the patient is on active chemoreduction as it
restricts the blood supply to the tumor thus reducing the intra-
tumor concentration of the chemotherapeutic agent
Table 17. High-Risk Features in Retinoblastoma
High Risk Features on pathology where adjuvant chemotherapy
is indicated
• Anterior segment invasion
• Ciliary body infiltration
• Massive choroidal invasion (invasion ≥ 3 mm in basal
diameter or thickness)
• Full thickness scleral extension
• Extrascleral extension
• Retrolaminar optic nerve invasion
• Optic nerve invasion at line of transection
• Combination of optic nerve infiltration till any level (pre-
laminar/ laminar/ retrolaminar) and choroidal infiltration
(any thickness)
High Risk Features on pathology where adjuvant radiotherapy
is indicated (in addition to chemotherapy)
• Full thickness scleral extension
• Extrascleral extension
• Optic nerve invasion at line of transection
retinoblastoma is the orbital extension of the disease which
is evident at presentation either clinically or radiologically.
Most of the patients present with proptosis, or a large
fungating mass which bleeds on touch. Tumor necrosis
causes inflammation of the surrounding tissues and the
patient may present with sterile orbital cellulitis. Secondary
orbital retinoblastoma occurs in an enucleated socket after
an uncomplicated surgery. It may present as an orbital
mass with an unexplained displacement of the implant,
or a palpable orbital mass. Accidental retinoblastoma
occurs in the event of an inadvertent perforation of the eye
harboring retinoblastoma. This can occur due to improper
enucleation technique, or various intraocular surgeries in
an eye with unsuspected intraocular retinoblastoma. Overt
orbital retinoblastoma refers to previously unrecognized
extrascleral or optic nerve extension discovered during
enucleation as an episcleral nodule, or an enlarged and
inelastic optic nerve with or without nodular optic nerve
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Table 16. Enucleation
Enucleation is the removal of the eyeball, and is usually
followed by replacement of the orbital volume using one of the
several types of implants available including acrylic, silicone and
hydroxyapatite implants, each with their own advantages and
limitations.
Enucleation by the myoconjunctival technique with a silicone
orbital implant is a safe and cost-effective procedure with
prosthesis motility comparable to biointegrateble implants while
minimizing the complications. This technique may also be used
in those requiring periorbital radiotherapy following surgery.
• The surgery is usually performed under general anesthesia.
• A lateral canthotomy is performed.
• A 360 degree peritomy is done using a blunt tipped Westcott
scissors, cutting as close to the limbus as possible.
• The underlying posterior Tenon’s layer is undermined in all
four quadrants in a spreading action using a blunt tipped
tenotomy scissors.
• Each of the recti muscles is identified, hooked and double-
tagged, first with 6-0 silk suture and then with 6-0 Vicryl
suture. 6-0 silk sutures serve as traction sutures while 6-0
Vicryl sutures would later be used to suture the muscles
through the conjunctiva.
• Each of the recti muscles is then transected at a point between
the two sutures using a radiofrequency probe.
• Superior oblique and inferior oblique muscles are transected
and allowed to retract posteriorly.
• A conjunctival relaxing incision is made for easy
manipulation.
• The eyeball is then prolapsed between the blades of the
speculum.
• With a forward traction on the eyeball using the 4 silk
sutures, a gently curved blunt tipped tenotomy scissors is
passed along the lateral wall and the optic nerve is strummed
along its length.
• With one bold cut, the optic nerve is transected just a little
anterior to the superior orbital fissure, to gain a good optic
nerve length and at the same time to avoid injuring the
superior orbital fissure contents.
• After achieving adequate hemostasis, an appropriate sized
silicone orbital implant is placed posterior to posterior
Tenon’s.
• Posterior Tenon’s is closed with interrupted 6-0 vicryl
sutures.
• Each of the Recti muscles is sutured through the conjunctiva
in its respective fornix, and these sutures are called the
myoconjunctival sutures.
• Anterior Tenon’s is closed with interrupted 6-0 Vicryl
sutures.
• Conjunctival closure is done in a continuous key-suturing
pattern with 6-0 Vicryl suture.
• An appropriate sized conformer is placed and a median
tarsorrhaphy done with 6-0 Vicryl suture.
• The suture tarsorrhaphy is removed after 1 week and a
prosthesis can then be placed in the socket after 6 weeks.
sheath. Microscopic orbital retinoblastoma is identified on
histopathological examination of the enucleated eyeball as
full thickness scleral infiltration, extrascleral extension or
invasion of the optic nerve.
The presence of orbital disease is generally known to carry a
poor prognosis. Orbital disease increases the risk of systemic
metastasis by 10-27 times and the mortality rates range
from 25 to 100%.30 However, with an intensive multimodal
management and careful monitoring, patients with orbital
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Table 18. Orbital Retinoblastoma: Classification
1. Primary Orbital Retinoblastoma
Clinical or radiologically detected orbital extension of an
intraocular retinoblastoma at the initial clinical presentation,
with either optic nerve involvement or scleral extension of
the tumor.
2. Secondary Orbital Retinoblastoma
Orbital recurrence following uncomplicated enucleation
for intraocular retinoblastoma, presenting as unexplained
displacement, bulge or extrusion of a previously well-fitting
conformer or a prosthesis.
3. Accidental Orbital Retinoblastoma
Inadvertent perforation, fine-needle aspiration biopsy or
intraocular surgery in an eye with unsuspected intraocular
retinoblastoma are considered as accidental orbital
retinoblastoma.
4. Overt Orbital Retinoblastoma
Previously unrecognized extrascleral or optic nerve
extension discovered during enucleation as an episcleral
nodule, or an enlarged and inelastic optic nerve with or
without nodular optic nerve sheath.
5. Microscopic Orbital Retinoblastoma
Full thickness scleral infiltration, extrascleral extension or
invasion of the optic nerve on histopathologic evaluation of
an eye enucleated for intraocular retinoblastoma.
Figure 9: Multimodal management in orbital retinoblastoma (A) External
photograph of primary orbital retinoblastoma taken during examination
under anesthesia (B) Axial computed tomography image displaying
extraocular extension of the intraocular tumor (C) After 12 cycles of doses
of high-dose chemotherapy, external beam radiotherapy and enucleation
(D) Healthy child cured of orbital retinoblastoma, with a well-fitting
prosthesis
disease are known to do well (Table 19) (Figures 9A-D).
Metastatic Retinoblastoma
With an incidence of less than 5% of all retinoblastoma cases,
metastatic retinoblastoma is most often seen in developing
countries. It usually occurs as a relapse following enucleation
for intraocular retinoblastoma, especially in those who had
high risk pathologic features.31 Most commonly, metastasis
occurs to the central nervous system (CNS), bone and bone
marrow. The metastasis occurs in one of the three ways-
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Recent Advances
Table 19. Orbital Retinoblastoma: Treatment
Baseline investigations:
• CT or MRI to assess the tumor extent
• Bone marrow biopsy
• Cerebrospinal fluid cytology
Treatment:
Multimodal management involving chemotherapy, surgery and
radiation therapy is employed. Chemotherapy is essential for
chemoreduction and to prevent systemic metastasis, surgery to
reduce the tumor load and clear the orbit of most of the tumor,
and radiation to take care of the residual disease and prevent
orbital recurrence.
Primary Orbital Retinoblastoma
• Neoadjuvant high dose chemotherapy is given for 3 cycles
• Residual disease is assessed by CT or MRI
• If orbital retinoblastoma has resolved, enucleation is
performed. If orbital retinoblastoma has not resolved, no
surgery is done at this stage and 3 more cycles of high dose
chemotherapy are given
• Residual disease is again assessed by CT or MRI
• If orbital retinoblastoma has resolved, enucleation is
performed at this stage. In case there is residual orbital
disease even after 6 cycles, exenteration is performed
• EBRT given to the orbit (45-50 Gy)
• Adjuvant high dose chemotherapy are given for 6 or 9 cycles,
to complete a total of 12 cycles
Secondary Orbital Retinoblastoma
• Neoadjuvant high dose chemotherapy is given for 3 cycles
• Residual disease is assessed by CT or MRI
• If orbital retinoblastoma has regressed significantly, excision
of the residual mass is performed. If orbital retinoblastoma
has not resolved, no surgery is done at this stage and 3 more
cycles of high dose chemotherapy are given
• Residual disease is again assessed by CT or MRI
• If orbital retinoblastoma has resolved, excision of the orbital
mass is performed at this stage. In case there is significant
orbital disease even after 6 cycles, exenteration is performed
• EBRT given to the orbit (45-50 Gy)
• Adjuvant high dose chemotherapy are given for 6 or 9 cycles,
to complete a total of 12 cycles
Accidental Orbital Retinoblastoma
• If the intervention is limited such as a needle biopsy and the
tumor is not advanced, high dose chemotherapy is given
for 6 cycles and the patient carefully monitored at frequent
intervals
• If the intervention is limited such as a needle biopsy and the
tumor is advanced, enucleation with an en bloc excision of
the conjunctiva at the needle site is performed and adjuvant
high dose chemotherapy is given for 6 cycles and the patient
carefully monitored at frequent intervals
• If the intervention is extensive such as pars plana vitrectomy,
enucleation with an en bloc excision of the conjunctiva
overlying the ports is performed and adjuvant high dose
chemotherapy is given for 6 cycles and the patient carefully
monitored at frequent intervals
• EBRT may be given in each case depending on the nature
of the disease, type and extent of the intervention and the
findings at subsequent follow-ups, a decision best left on the
treating doctor’s expertise
Overt Orbital Retinoblastoma
• If an extrascleral extension is macroscopically visualized
during enucleation, special precaution is taken to excise
the nodule completely along with the eyeball, also with the
overlying Tenon’s capsule in the involved area

Recent Advances
• If optic nerve extension is suspected during enucleation and
the nerve stump obtained is short, extra effort to excise an
additional length is made
• In both cases, EBRT is given followed by 12 cycles of adjuvant
high dose chemotherapy
Microscopic Orbital Retinoblastoma
• If microscopic full thickness scleral involvement and/ or
extrascleral extension and/ or optic nerve involvement up to
the level of transection is detected, EBRT is given followed
by 12 cycles of adjuvant high dose chemotherapy
Follow-up
• CT or MRI 6-monthly to look for tumor recurrence
• Bone marrow biopsy 6-monthly
• Cerebrospinal fluid cytology 6-monthly
by direct dissemination into the CNS via the optic nerve,
choroidal invasion and hematogenous spread, or orbital
extension with lymph node involvement and hematogenous
spread. Bony metastasis, usually involving the long bones
or the craniofacial bones, causes non-tender palpable mass.
Cerebrospinal fluid cytology, bone marrow evaluation and
whole body imaging are done in all cases of metastatic
retinoblastoma for staging the disease. Use of high-dose
chemotherapy with autologous stem cell rescue (ASCR) has
offered some encouraging results. However, most of the
experience is in stage 4a disease that does not involve the
CNS. The use of radiotherapy and intrathecal chemotherapy
for CNS lesions have been recommended, although the
prognosis for such advanced metastatic retinoblastoma
continues to remain grim.31
Prenatal Genetics
To prevent transmission of the disease from parents to
offspring, genetic testing for germline mutations can be
done at specialized laboratories. RB1 is the only gene
that is implicated in retinoblastoma. However, there are
different types of mutations affecting this gene. Direct
DNA sequencing detects 75% of the mutations, and PCR
amplification detects yet another 20% of the mutations.
Peripheral blood lymphocytes or tumor tissue, when
available, are sampled for the detection of the mutation.
In heritable retinoblastoma, once the mutation is identified
in the lymphocytes, the presence of the same mutation is
tested in the fetus (sibling or offspring) by chorionic villus
biopsy or amniocentesis. If the mutation is found, a decision
to terminate the pregnancy can be made.
In non-heritable retinoblastoma, if the tumor tissue is
available from an affected individual, it can be sampled
to detect the type of mutation. If the same mutation is also
found in the blood of the patient, the individual is positive
for germline mutation and an offspring can be tested for
the same mutation. However, if no mutation is found in
the blood, the tumor is nongermline (sporadic), without
any risk of transmission of the disease to the offspring. In
case no tumor tissue is available, lymphocytes are sampled
for the type of RB1 mutation, but the interpretation of a
negative result in these cases is difficult. Either the patient
has a sporadic retinoblastoma, or a germline mutation that
escaped detection by the currently available techniques.
Preimplantation genetic testing for carriers of mutation
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involves the identification of RB1 mutation in a blastomere (8-
cell embryo) which is obtained by in vitro fertilization (IVF)
technique. The small material is amplified by polymerase
chain reaction (PCR) and the blastomere without the RB1
mutation maybe implanted for a successful pregnancy.3
Conclusion
The management of retinoblastoma revolves around
having a sound knowledge of the disease, choosing the
best treatment for the patient among the various available
options and careful monitoring for recurrences. Enucleation
should be performed when deemed necessary in advanced
retinoblastoma with no visual prognosis, without needless
overenthusiasm for globe salvage in advanced tumors.
Specific precautions during the surgery, use of a primary
implant for cosmesis, and post-enucleation evaluation of
histopathologic HRFs and adjuvant therapy, as appropriate,
achieve optimal life salvage. Primary focal therapy with
laser, TTT or cryotherapy for peripheral tumors can be used
for ICRB group A tumors in visually noncritical locations.
IVC continues to be the standard treatment for ICRB groups
B to D, and for bilateral retinoblastoma. Appropriate use of
high-dose protocol and concurrent POC can help salvage
group D and E eyes with diffuse vitreous seeds. IAC is a
very promising treatment with high success for advanced
retinoblastoma, but the cost factor must also be taken into
consideration. IVitC should be performed with safety-
enhanced technique. Radiation therapy should be employed
only when indicated. Retinoblastoma has a very high cure
rate, and is best managed in an integrated retinoblastoma
clinic under the watchful monitoring of an expert ocular
oncologist. The recent advances in management of
retinoblastoma and a holistic approach have rendered it
eminently curable - prognosis for life salvage is now around
98%, with 90% eye salvage and 80% vision salvage.
Cite This Article as: Rao R, Honavar SG. Recent Developments in
Retinoblastoma . Delhi J Ophthalmol 2016;27;50-61.
Acknowledgements: None
Date of Submission: 28/05/2016 Date of Acceptance: 03/06/2016
Conflict of interest: None declared
Source of Funding: Nil
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Corresponding author:
Santosh G Honavar MD, FACS
Director, Ocular Oncology Service
National Retinoblastoma Foundation, Centre for Sight
Ashoka Capitol, Road No 2, Banjara Hills
Hyderabad 500034, India
Email: santosh.honavar@gmail.com